1. Field of the Invention
The present invention relates to skin condition-improving compositions for topical application to the skin, which comprises human growth hormone as an active ingredient and a method for improving skin conditions of a human.
2. Description of the Related Art
It is a general conception that macromolecules, especially hydrophilic proteins such as human growth hormone (molecular weight of about 22 kD), can not pass through the skin stratum corneum. A molecular weight that can be delivered efficiently and safely through the skin epidermis is generally recognized to be no more than about 500 dalton to the intact skin, or at most 2 kD even with the help of skin penetration enhancers. Accordingly, applying a protein such as human growth hormone topically to the intact skin and expecting cosmetic (for example, anti-wrinkle, etc.) or medical (for example, anti-acne, etc.) efficacies by the action of the protein have been considered non-sensible.
Some rare attempts have been made to deliver proteins to the dermal layer of the skin by topical application of liposomes encapsulating the proteins. There also have been some controversy over which routes the protein-encapsulating liposomes take to reach the dermis, one through the stratum corneum or the other through the hair follicles, when applied topically to the skin. For delivery through hair follicles, either a carrier in the form of liposomes or a lipid composite comprising lipids such as fatty acids has been reported to be favorable. In addition, although efficiencies turned out to be much lower, an aqueous solution containing an organic solvent such as ethanol, or an aqueous solution containing a polymer such as polyethylene glycol, has also been tested as a facilitating medium for delivery through hair follicles. With respect to efficiencies of delivering proteins through the skin using liposomes carrying proteins, a general principle has not been established yet, because cases of liposomal protein deliveries have been scarce and even in those rare cases, the efficiencies of protein deliveries varied widely depending on the empirical choices of the target proteins and the nature of the liposomes used. One thing to note is that, although the idea of delivering proteins through hair follicles is gaining more acceptances, even when a protein is delivered in a liposome-encapsulated form, liposomes may not pass through the infundibular portion of the hair follicles intact, rather they may undergo different morphological transformations or phase transitions owing to, first, the characteristics of the phospholipids conferring inside and outside pH's and charge valences of the liposomes, second, those of the proteins attached to or encapsulated by the liposomes, and third, those of the constituting ingredients of the surrounding tissues making up the hair follicles. Thus as a whole, these three factors and their complex interactions seem to determine follicular delivery efficiencies of the liposomes containing the proteins in question through empirical formulations rather than by a general guiding principle at the moment. What is particularly noteworthy with regard to the present invention is the existence of a report stating human growth hormone receptors are located on the living cell layers of the epidermis and throughout the ancillary organs and tissues constituting and surrounding the hair follicles.
Human growth hormone is secreted from the anterior lobe of pituitary gland and circulates with blood while it influences each organ of the human body. In the growth stage of a human, it is particularly involved in the growth of skeleton, an increase in muscles, the decomposition of fat, the growth of the internal organs, sexual growth and the like. In addition, it was suggested that when human growth hormone was administered by injection to adults at a physiological range of blood concentration, it would show various effects, such as the strengthening of the heart circulatory system, the enhancement of exercise ability, the strengthening of muscles, the reduction in abdominal fatness, the increase in libido, the improvement of improvement of arteriosclerosis, and the improvement of geriatric depression. It is known that the effects of human growth hormone on the human body are not caused by the human growth hormone itself, but rather are caused by the action of insulin-like growth factor-1 (IGF-1), the expression of which is stimulated by human growth hormone and which is produced mainly in the liver and secreted into blood. This is because the blood half-time of human growth hormone is about 15 minutes, whereas the blood half-time of IGF-1 is about 20 hours, indicating that IGF-1 can be lasting much longer than human growth hormone. Concretely speaking, human growth hormone secreted from pituitary gland binds to human growth hormone-binding protein present in blood, migrates with blood circulation, and meets a human growth hormone receptor present in each tissue of the human. At this time, the human growth hormone is liberated from the human growth hormone-binding protein while it binds to the human growth hormone receptor, and the synthesis and secretion of IGF-1 are stimulated as a result of signaling caused by the binding. The IGF-1 secreted into blood then binds to an IGF-1 binding protein, and circulates with blood flow while it binds to an IGF-1 receptor present in each tissue of the human body, thus exhibiting various physiological effects caused by the secretion of human growth hormone. Accordingly, if the effect of the injection agent human growth hormone on the skin will be actually shown, it will be an effect caused by the action of IGF-1, and thus will necessarily depend on the presence or absence of the IGF-1 receptor on the surface of dermal cells that can be brought into direct contact with blood. Even if the skin is considered to be influenced directly by human growth hormone, but not by IGF-1, the influence will necessarily be transferred by the human growth hormone receptor present at sites which are in contact with blood. Therefore, it is considered that expecting any effect on the skin by applying human growth hormone (having molecular size that cannot pass through the skin) together with cosmetics to the normal skin surface that is not brought into direct contact with blood is not common sense. The present invention is a first report that, through a method of applying human growth hormone in the form of a cosmetic preparation to the normal skin surface that is not in direct contact with blood, but not a method of transferring the effect of human growth hormone through blood, the human growth hormone can show cosmetic and medical effects on the skin, such as the improvement of acne, wrinkles, atopic skin, skin damage caused by UV light, dark spots, freckles, dry skin and oily skin, the reduction of hair follicles, and the stimulation of hair growth.
Skin tissue consists of the epidermis, the dermis and the hypodermis. The epidermis determines the properties of the skin, and is frequently susceptible to damage directly from the external environment, and thus the repair and regeneration of the epidermis are highly important. The epidermis consists of a layer of epidermal cells. The skin epidermal cells are also called “keratinocytes”, because the skin epidermal cells synthesize intermediate filament protein keratin that strengthens the epidermis, during their differentiation. These cells are layered with differentiation while migrating toward the epidermis, and become flat while organs inside the cells gradually disappear and they become dead cells. A cell layer located at the innermost portion of the epidermis is contiguous to the basal lamina and called the “stratum basale”, and the cells forming the layer are called “basal cells”, among which epidermal stem cells are present. The cells of the stratum basale differentiate into the epidermis while they sequentially form the stratum spinosum, the stratum granulosum, the stratum lucidum and the stratum corneum, the stratums being divided into a living cell layer at the lower position with respect to the stratum granulosum, and a dead cell layer at the upper position. Flattened scale-like tissues outside the stratum corneum are also called “squames” where keratins are densely filled. Cells located from the outside of the stratum granulosum to the stratum corneum are reinforced with a layer of cross-linked protein whose plasma membrane is thin and tough. While the epidermal cells are proliferated from the epidermal stem cells and differentiated into the stratum corneum, they are internally reinforced by the cross-linking of keratins and are also linked by keratins with desmosomes firmly linked with other cells in the same layer so as to maintain the entire layer structure thereof. The epidermal cells are differentiated into the outer epidermis while they produce and secrete lipid so as to form double-layered tissue on a plasma membrane cornified with protein, thus preventing the skin surface from the external environment, like saran wrap. Since the human epidermis is replaced at two-week interval, the proliferation ability of skin stem cells forming the epidermis can be considered to be huge.
It was recently reported that the multipotent stem cells of the skin are located at the bulge region, which lies just below the sebaceous gland of hair follicles. These bulge stem cells serve as the basis for making epidermal stem cells, hair matrix stem cells, and sebaceous glands stem cells. The bulge stem cells are located only in the bulge region and express a special combination of protein while maintaining their property as stem cells. The epidermal stem cells maintain the epidermis while they proliferate and differentiate. When a hair falls out, the hair matrix stem cells will proliferate and differentiate to make a new hair. However, the epidermal stem cells, the hair matrix stem cells or the sebaceous glands stem cells have limitations in their proliferation ability or the ability to maintain the ability of stem cells, and thus, for example, most of the epidermal stem cells will differentiate after they proliferate 3-6 times. On the other hand, although the bulge stem cells proliferate slower than the other three stem cells, it seems that the bulge stem cells can indefinitely proliferate during the life of human beings while making the epidermal stem cells, the hair matrix stem cells and the sebaceous glands stem cells and, at the same time, maintaining their stem cell character. The fact that the location of expression and action of human growth hormone is the location of the bulge stem cells has been disclosed for the first time through the present invention, and this disclosure is quite significant considering that the human growth hormone has the effect of improving various skin conditions as described in the present invention.